The present invention is directed to galanthamine-analogues having cholinesterase inhibiting properties and their preparation and use for treatment of Alzheimer""s disease and related dementias, some of the analogues are novel.
U.S. Pat. No. 4,663,318 issued on May 5, 1987 describes the use of galanthamine for the treatment of Alzheimer""s disease and related dementias.
Published European Patent Application 236684 describes the use of galanthamine and certain analogues for the treatment of Alzheimer""s disease and related dementias, such analogues are those wherein the hydroxy group of naturally occurring galanthamine may be replaced by methoxy, ethoxy or lower alkanoyloxy, the methoxy group of galanthamine may be replaced by hydrogen, methoxy, ethoxy or lower alkanoyloxy and the N-bonded methyl group may be replaced by other straight or branched chain alkyl groups, cyclopropylmethyl, cyclobutylmethyl or allyl groups or substituted lower alkyl phenyl groups or wherein other hydrogen atoms are substituted by chloro or fluoro atoms.
The literature shows the epigalanthamine wherein the hydroxy group is in the equatorial position so that hydrogen bond stabilization of structure is not possible has an anti-cholinesterase activity of only 10% of galanthamine. (Chem. Abstr., 77, 109461s)
A number of galanthamine analogs occur naturally or have been obtained from natural products including the following compounds described in the text book The Alkaloids (edited by R. H. F. Manske published by Academic Press, NY, 15th Edition): narwedine:
(also referred to sometimes as galanthaminone) 
Narwedine has been reported to have weak anticurare activity at 3 mg/kg (Chem. Abstr., 78, 131941r) and to have cholinergic effects on respiration and heart activity, 50-80% lower than galanthamine (Chem. Abstr., 80, 103864r), Schmidt et al in Acta. Biol. Med. Ger. 7: 402-410 (1961) report that the anticholinesterase activity of Narwedine is less than 1% of that of galanthamine.
(xe2x88x92) N-demethylgalanthamine: 
galanthamine-O-methyl ether: 
childanthine: 
lycoramine: 
It has been reported that the concentration of lycoramine required to stimulate EEGxe2x80x94recorded activity is about five times that required for galanthamine (Chem. Abstr., 62, 15306e).
deoxylycoramine 
habranthine: 
anhydrogalanthamine: 
anhydro-O-demthylgalanthamine: 
and N-mesityl and N-benzyl derivatives of galanthamine.
Reference is also made to compounds of the formulae: 
The latter compound has been reported to have activity similar to that of galanthamine (J. Chem. Soc., (C) 1043 (1971).
An earlier edition of this book had also referred to (+) N-demethyldihydrogalanthamine of the formula: 
N-demethyldihydrogalanthamine is described by Kametani et al in J. Heterocyclic Chem., 10, 35-37 (1973). The same paper also refers to galanthamine O, N-diacetate leucotamine 
and its O-methyl and O-methyl acetic acid ester are described by Kobayashi et al in Chem. Pharm. Bull., 33:, 5258-5263 (1985).
O-demethyldihydrogalanthamine (also known as O-demethyllycoramine) and O-demethylgalanthamine (sanguinine) are also described by Kobayashi et al in Chem. Pharm. Bull., 28:, 3433-3436 (1980).
Subsequently, Kobayashi disclosed the extraction of O-demethyl lycoramine (also known as dihydrosanguinine) from bulbs of Lycoris radiata Herb. (Chem. Pharm. Bull., 28: 3433-6 (1980), Chem. Abstr. 95,25351.
A bromo-narwedine of the formula: 
is described as an intermediate in the synthesis of galanthamine by Kametani et al in Chem. Comm., 425 (1969) and J. Chem. Soc. (C), 2602 (1969).
Chem. Abstr. 61,14727 g Chem. Pharm. Bull., 12:1012-20 (1964) describes the production of compounds of the formula: 
wherein R may be hydrogen, methyl or ethyl.
A dihydro derivative of childanthine obtained by hydrogenation of the parent compound is described by Boit in Chem. Ber, 90: 57-9 (1957): Chem. Abstr., 51,8120f.
Chemical Abstracts 81 638193 describes n.m.r. studies on dihydrogalanthamine and its acetic acid esters.
Fales, Giuffrida and Wildman in Journal of American Chemical Society, 78:4145 (1956) report that the bulbs of King Alfred daffodils contain the known alkaloids galanthamine, galanthamine, lycoramine, haemolycoramine, haemanthamine and narcissamine and a new alkaloid pseudo lycorine. They also reported that narcissamine has been shown to be N-demethyl galanthamine.
Latho and Fales in J. Am. Chem. Soc., 4434-4438 (1964). report that contrary to what had previously been believed, narcissamine was in fact a mixture of N-demethylgalanthamine and N-demethyllycoramine.
Tetsuji Kametani et al. in Yakuyaku Zasshi 12: 1353-1358 (1977) describe a synthetic route to convert 2-benzazepin-3-ones to galanthamine analogues in anticipation of them having analgesic activity. Among the analogues including those where the phenol ring is substituted by bromine or hydroxy methyl on the carbon atom adjacent to the phenolic hydroxy group.
In German OS 2945161 there is described the production of certain narwedine type enones and their derivatives, including those where the benzene ring is bromo-substituted and the nitrogen containing ring contains a keto group adjacent to the nitrogen.
Shimizu et al in Heterocycles, 8: 277-282 (1977) (abstracted in Chemical Abstracts, 88, 136821t) describe certain narwedine derivatives used as intermediates having the following formulae: 
Irwin and Smith in Arch. Int. Pharmacodyn., 127:314-330 described the cholinesterase activity of galanthamine and some of its analogues including lycoramine acetate methiodide, neopin methiodide (both of which were ineffective) and deoxydemethyl lycoramine methiodide (which demonstrated good activity) and deoxylycoramine (which exhibited some activity). It was hypothesized that the presence of a free hydroxy group in the cyclohexane ring conferred activity on the molecule since the acetylation of this group led to a drop in activity.
In J. Pharm. Exp. Ther., 134:53 (1961), Irwin, Smith and Hein expanded on the work just described and reported that replacement of the hydroxyl group of deoxydemethyl lycoramine methiodide by a carbamate group resulted in useful pharmacological activity.
Subsequently, Irwin and Hine, J. Pharm. Exp. Ther., 136:20 (1962) described the activity of a number of carbamates including deoxydemethyl lycoramine carbamate on cholinesterase activity in rat brain.
Subsequently, Somers et al. in Neurology, 13:543 (1663) reported that some of Irwin""s compounds were useful in treating myasthenia gravis.
One of the characteristics of Alzheimer""s disease and certain other considerations is a reduction in the amount of acetyl choline in the brain (see for example, Perry et al British Medical Journal 2:1457-1459 (1978). Acetylcholine is a compound that is involved in the transmission of electrical impulses between nerve endings. Excessive amounts of acetyl choline cause undesirable side effects so that the brain also contains a cholinesterase enzyme to prevent build up of acetyl choline. Thus, if the production of acetyl choline cannot be increased, one way to approach the problem of low acetylcholine levels is to reduce the amount or activity of the cholinesterase so that such acetyl choline is present may be used. Unfortunately, finding a useful treatment for Alzheimer""s disease is not simply a matter of feeding a patient with a cholinesterase inhibitor. To be effective, a compound must pass the blood brain barrier easily and distribute itself between the central and peripheral nervous systems in such a way that its effect is mainly central, and it must not have significant side effects. It must have a reasonably long half life in the brain. It must be reversible to at least some extent (otherwise nerve gasses would be effective treatmentxe2x80x94which they are not) and it must be able to be formulated in a way that makes it suitable for use by those suffering from the disease. Loss of acetyl choline in the brain can exist alongside other conditions where Alzheimer""s disease is not the primary indication where the same neurochemistry exists. References herein to xe2x80x9crelated dementiasxe2x80x9d are intended to include to such situations. Similar problems of cholinergic deficiency and dementia accompanied by plaques and tangles in the brain also arise in the later stages of Down""s syndrome which is similarly a xe2x80x9crelated dementiaxe2x80x9d.
From one aspect, the present invention relates to the use of compounds of the formula I to treat Alzheimer""s disease and related dementias 
wherein the broken line represents an optionally present double bond in one of the two portions shown, R1 and R2 are each selected independently from the group consisting of hydrogen, hydroxyl, amino or alkylamino or phenyl amino, cyano, sulfhydryl, alkoxy preferably of 1-6 carbon atoms, alkylthio, aryloxy, arylthio, R5-substituted aryloxy, R5-substituted arylthio, aralkoxy, aralkylthio, R5-substituted aralkoxy, R5-substituted aralkylthio, aryloxymethyl, R5-substituted aryloxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy, R5-substituted benzoyloxy, aryloxy carbonyl and R5-substituted aryloxy carbonyl and corresponding carbonates, a mono or dialkyl or aryl carbamyl group or hydroxy methyl, R1 may also by alkyl of up to 14 carbon atoms, R2 may also be halo such as iodo or may be carboxymethyl provided that at least one of R1 and R2 is hydroxy, amino or alkylamino unless R7 or R8 is hydroxymethyl,
R3 is hydrogen, straight or branched chain alkyl, preferably of 1-6 carbon atoms, cycloalkyl methyl, alkylphenyl, R5-substituted alkylphenyl, heterocyclic such as xcex1- or xcex2-furyl, xcex1- or xcex2-thienyl or thenyl, pyridyl, pyrrolyl pyrazinyl or pyrimidyl groups, alkyl heterocyclic and Rxe2x80x2-substituted heterocyclic, where Rxe2x80x2 is alkyl or alkoxy or
R3 is alkanoyl of 1 to 8 carbon atoms or aroyl wherein the aryl group is of 6 to 10 carbon atoms, the alkyl and aryl portions of said groups optionally being substituted by R5 groups as hereinafter defined or R3 is the residue of a compound having adrenergic or monoamino oxidase activity and is selected from the group consisting of 
wherein Hal is a halogen, preferably chloro, p is ), 1 or 2, q is 0 or 1, r is 0 or 1 and Z is selected from the group consisting of 
wherein Q is hydrogen or hydroxy, L is hydrogen or C1-4 alkyl, G is hydrogen, C1-4 alkyl, alkylphenyl wherein said phenyl group is optionally substituted by hydroxy or methylene deoxy, or is alkyl alkanylamino 
wherein G is as defined above, 
each R4 is independently selected from hydrogen, hydroxyl, sulfhydryl, alkyl, aryl, aralkyl, alkoxy, thioalkoxy, aryloxy, thioaryloxy, alkylarlyoxy, alkylmercaptoaryloxy, nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo iodo and trifluoromethyl, and R5 is selected from the same groups as R4,
R6 is hydrogen, halo, trifluoromethyl or alkyl of 1 to 4 carbon atoms,
R7 is selected from the same groups as R4 or may be hydroxy alkyl of 1-2 carbon atoms,
R8 is hydrogen or hydroxymethyl,
R9 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl, or when R2 is hydroxyl R9 may be a moiety of formula I wherein R9 is hydrogen and R2 is a linking bond; or R2 and R9 may jointly form a semicarbazone, oxime, phenylhydrazone or a keto group
X is oxygen or NR5,
Y is nitrogen,
and methylenedioxy derivatives thereof with the proviso that when X is O, R3 is not methyl when R1 is methoxy, R2 is hydroxy, and all R4 are hydrogen or a pharmaceutically-acceptable acid addition salt thereof. When there is no unsaturation in the 1,2 carbon bond, R2 is preferably oriented axially to the cyclohexane ring. When R and R9 jointly form a single group it is normally desirable that R1 be hydroxy or amino.
Preferably the aryl groups are phenyl or naphthyl or in the case of R2 when this is a carbamate group, 1-naphthyl groups, the aryloxy groups are phenoxy groups, the aralkyl groups are benzyl groups and the aralkyloxy groups are benzyloxy groups.
Preferred compounds include those wherein R1 and R2 are each selected from
H, OR, SH, NH2 or NHR 
xe2x80x94CH2OH, xe2x80x94Oxe2x80x94CONHR 
wherein R is-alkyl 1-6 carbon atoms, phenyl or naphthyl R5-substituted phenyl naphthyl or benzyl wherein R10 is hydrogen, alkyl or alkoxy,
R3 is xe2x80x94H, or branched on linear lower alkyl or 
wherein n is 3, 4 or 5 or 
wherein R10 is as defined above.
Preferred R3 groups are normally electron-donating such as lower alkyl groups such methyl and tertiary butyl and phenyl and substituted phenyl groups such as hydroxy phenyl, p-alkoxy phenyl, p-amino phenyl and p-alkyl phenyl. However, groups such as benzyl and benzoyl may also be of use.
X is preferably oxygen and Y is nitrogen.
When used herein the term xe2x80x9clower alkylxe2x80x9d means alkyl of 1-6 carbon atoms, preferably 1-4 carbon atoms, most commonly methyl or ethyl.
Compounds likely to be of particular use are those wherein R3 is hydrogen, lower alkyl or cyclopropyl methyl and R1 and R2 are each independently hydroxy, lower alkoxy, lower alkanoyl or benzoyl or carbamate groups and the analogous dihydro compounds wherein the cyclohexene ring of galanthamine is saturated. Thus, R1 may typically be hydroxy, methoxy, ethoxy or carbamoyl of the formula CONHR11 wherein R11 is methyl, ethyl, n-propyl, n-butyl, n-valeroyl, phenyl, naphthyl or fluoro or nitro substituted phenyl or naphthyl, R2 may typically be hydroxy, methoxy, ethoxy, acetyloxy, propionoyloxy, n-valeroyloxy, i-valeroyloxy, or CONHR11 wherein R11 is as defined above. R3 is typically hydrogen, methyl or ethyl.
Particularly preferred compounds include childanthine, lycoramine, galanthamine esters and galanthaminexe2x80x94and O-demethyl galanthamine carbamates and the corresponding N-demethyl compounds. The galanthamine and O-demethyl galanthamine carbamates are believed to be novel compounds.
One class of compounds according to the present invention are those of the formula: 
wherein R1 is as defined above, preferably hydroxy, lower alkoxy, aryloxy, substituted aryloxy, benzyloxy or R3 substituted benzyloxy, amino, alkyl amino or an alkyl or aryl carbamyl group.
For example, such compounds include O-demethyl, N--demethylgalanthamine; O-ethyl, O-demethyl, N-demethylgalanthamine; O-phenyl, O-demethyl, N-demethylgalanthamine; and O-benzyl, O-demethylgalanthamine. Useful carbamates may include phenylcarbamyl O-demethyl, N-demethylgalanthamine; mono xcex1-naphthylcarbamyl O-demethyl N-demethyl galanthamine and dimethylcarbamyl O-demethyl, N-demethylgalanthamine.
A second class are those of the formula: 
wherein R2 is hydroxy, lower alkoxy, aryloxy, mono or di alkyl or aryl carbamates R3 substituted aryloxy benzyloxy or R3 substituted benzyloxy or an alkyl or aryl carbamyl group and R3 is hydrogen or alkyl of 1-6 carbon atoms such as methyl ethyl, methyl cyclopropyl, benzyl or benzoyl or R3-substituted benzyl or benzoyl. Suitable R3 groups are as described above. Such compounds include O-demethylgalanthamine childanthine; O-demethylgalanthamine; 2-O-methyl ether; O-demethyl galanthamine-2-O-ethyl ether; O-demethylgalanthamine-2-O-benzyl ether; O-demethylgalanthamine-2-O-phenyl ether and O-demethyl N-demethylgalanthamine, 2-naphthyl carbamate; O-demethylgalanthamine-2-(lower alkyl) carbamates such as n-butyl carbamate, O-demethylgalanthamine-2-dimethyl carbamate and O-dimethylgalanthamine-2-diethyl carbamate wherein the carbamyl group is bonded to the oxygen of the cyclohexene ring, and the corresponding N-demethyl and N-demethyl N-ethyl and N-demethyl N-cyclopropyl methyl and N-demethyl N-benzyl compounds.
O-Demethyl-N-demethyl-N-ethyl galanthamine; O-demethyl-N-demethyl-N-ethyl galanthamine, O-methyl, O-ethyl or O-benzyl ether wherein said etherification is in the 2-position; O-demethyl-N-demethyl-N-ethyl galanthamine phenyl, xcex1-naphthyl, dimethyl or diethyl carbamate wherein said carbamate substitution is in the 2-position; O-demethyl-N-demethyl-N-cyclopropyl methyl galanthamine, O-methyl, O-ethyl or O-benzyl ether wherein said etherification is in the 2-position; O-demethyl-N-demethyl-N-cyclopropylmethyl galanthamine, O-demethyl-N-demethyl-N-cyclopropylmethyl galanthamine, O-methyl, O-ethyl or O-benzyl ether wherein said etherification is in the 2-position; O-demethyl-N-demethyl-N-cyclopropylmethyl galanthamine phenyl, xcex1-naphthyl, dimethyl or diethyl carbamate wherein said carbamate substitution is in the 2-position; O-demethyl-N-demethyl-N-benzyl galanthamine; O-demethyl-N-demethyl-N-benzyl galanthamine, O-methyl, O-ethyl or O-benzyl ether wherein said etherification is in the 2-position, O-demethyl-N-demethyl-N-benzyl galanthamine phenyl, xcex1-naphthyl, dimethyl or diethyl carbamate wherein the carbamate substitution is in the 2-position.
A third class of compounds comprises those of the formula: 
wherein R1, R2 and R3 are as defined above, R1 typically being hydroxy, amino lower alkoxy, benzyloxy or R3 substituted benzyloxy, amino alkylamino or alkyl or aryl carbamyl, R2 is hydroxy, lower alkoxy, aryloxy, benzyloxy or an alkyl or aryl carbamyl group but is preferably hydroxy and R3 is typically hydrogen, methyl, ethyl, cyclopropylmethyl, phenyl, p-hydroxy phenyl, p-aminophenyl, p-alkoxyphenyl or p-alkylphenyl or benzyl.
Such compounds include, for example, O-demethyl lycoramine; N-demethyl, O-demethyl lycoramine; N-demethyl N-ethyl lycoramine; N-demethyl N-cyclopropylmethyl lycoramine; N-demethyl N-benzyl lycoramine; O-demethyl lycoramine ethyl ether; deoxy O-demethyl lycoramine; O-deoxy demethyl lycoramine, benzyl ether and dimethyl and phenyl carbamyl analogs of such compounds.
A further class comprising compounds of the formula: 
wherein R3 is selected from hydrogen, lower alkyl, cycloalkyl methyl or benzyl;
A further class of compounds are narwedine derivatives where R1 is hydroxy and R3 as defined above, typically hydrogen, lower alkyl, cycloalkyl methyl or benzyl. Such compounds many contain R4 and R6 substituents as noted above.
Compounds of the above formula I where R2 is hydroxyl and R9 is a moiety of formula I wherein R9 is hydrogen and R2 is a linking bond are compounds in which the structure of formula I has linked at ring position 2 a hydroxyl group and a second formula I structure wherein R2 is a bond linking the second formula I structure to said position 2 of the first and in said second formula I structure, R9 is hydrogen. Such compounds may be made by reacting a compound of formula I wherein R2 is hydroxyl to convert the hydroxyl to a halide, reacting the halide to form a Grignard compound, and reacting the latter with a galanthamine ketone.
Useful compounds may include the following: 
The novel compounds of the present invention in addition to their use for treatment of Alzheimer""s disease can find use in a variety of other circumstances where cholinesterase inhibition is desired.
Many compounds of the present invention may be obtained by effecting suitable conversions of galanthamine. Galanthamine has the structure: 
Compounds wherein R1 is other than methoxy can be obtained from galanthamine by demethylation to the corresponding phenol and, if desired, effecting subsequent conversion thereon. Demethylation may be effected with iodotrimethylsilane in accordance with the method described by M. E. Jung and M. A. Lyster in J. Org. Chem. 42 3761 (1977). Reaction with iodotrimethylsilane may be effected in any convenient solvent, for example, chloroform at moderate temperatures (typically 25-40xc2x0 C.) for several hours (e.g. 12-20 hours) to cleave the methyl group.
The phenol obtained by this reaction may be employed itself or used as an intermediate for the production of other active compounds. If it is desired to avoid effecting the same reactions at the allylic hydroxy group in the C ring as are to take place at the phenol group, that is produced by demethylation of the A ring, it is desirable to protect the allylic hydroxyl group when carrying out further interconversions. Suitable protection can be effected by converting the allylic hydroxyl group to its tetrahydropyranyl ether or 4-methoxytetra-hydropyranyl ether. Such ethers can be formed by reaction with dihydropyran or 4-methoxytetra-hydropyran in a solvent such as dichloromethane at room temperature, and in the presence of a strong organic acid such as p-toluenesulfonic acid. When desired, the protective groups can be removed, the tetrahydropyranyl group, for example, by treatment with methanol and Dowex-50 WX8 and the 4-methoxytetrahydropyranyl group by reaction with very dilute (e.g., 0.01N) hydrochloric acid.
The phenolic group obtained by demethylation of the methoxy group of galanthamine may readily be converted into an alkali metal salt by reaction with sodium or potassium hydroxide or reaction with sodium hydride in tetrahydrofuran. The salt so obtained may be xe2x80x9calkylatedxe2x80x9d by reaction with an appropriate alkyl, aryl, alkaryl or R5-substituted aryl or alkaryl or heterocyclic or R5 -substituted heterocyclic halide to produce a compound wherein R1 is alkoxy (other than methoxy), aryloxy, alkaryloxy, R5-substituted aryloxy, R5-substituted alkoxy or heterocyclic or R5-substituted heterocyclic. The reaction with the halide is typically run with excess halide in the absence of solvent or in a solvent such as dimethyl formamide or dimethylsulfoxide. For less reactive halides, the presence of a silver oxide catalyst may be desirable.
Reaction of the phenolic group with an isocyanate can be used to introduce a monoalkyl or monoaryl carbamyl group.
Dialkyl or diaryl carbamates may be obtained [by] from the mono alkyl or aryl carbamates by reaction with sodium hydride and an alkyl or aryl iodide. For example, the dimethyl carbamate can be obtained by reaction of the hydroxy group with methyl isocyanate followed by reaction with sodium hydride and methyl iodide.
Conversion of the phenolic group to an amino group, which can subsequently be alkylated by conventional means to produce a secondary amine if desired, can be effected by the Bucherer reaction using sodium bisulfite and ammonia.
The phenol group may be esterified, for example, with an acid anhydride or acid halide to produce an alkanoyloxy or aralkanoyloxy, R1 group.
Production of compounds wherein R1 is sulfhydryl or an alkyl-, aryl-, aralkylthio group can be effected by first converting the phenolic hydroxyl group obtained by demethylation of galanthamine to a thiol group. This can be effected, for example, by the Newman-Kwart rearrangement described, for example, in S. Patai ed xe2x80x9cThe Chemistry of the Thiol Groupxe2x80x9d Part 1 John Wiley and Sons, New York 1974 pages 201-206. This rearrangement is effected in three steps:
(1) conversion of the hydroxyl group to the O-aryl dialkylthiocarbamate by treatment with dialkylthiocarbonyl chloride;
(2) pyrolysis of the O-aryl dialkylthio-carbamate to the S-aryl dialkylthiocarbamate; and
(3) hydrolysis of this product to the aryl mercaptan.
The first stage reaction wish dimethylthio-carbamyl chloride may be effected by dissolving the phenol obtained by demethylation of galanthamine in aqueous potassium hydroxide at 10xc2x0 C. or below and then reacting this with dimethylthiocarbamyl chloride in tetrahydrofuran at temperatures not exceeding 12xc2x0 C. The solution is made alkaline and the O-aryl dimethyl-thiocarbamate is separated. This compound is pyrolyzed at 270-275xc2x0 C. for about 45 minutes in a salt bath, and treated with potassium hydroxide in ethylene glycol. The reaction is cooled, the product extracted and worked up.
The thiol group can be converted to an alkali metal salt if desired by reaction with sodium or potassium hydroxide or sodium hydride. This salt may be alkylated to produce compounds wherein R1 is alkylthio, arylthio, aralkylthio or alkarylthio by any one of a wide variety of alkylating agents, for example, as described by P. D. Boyer in J. Amer. Chem. Soc., 76:4331 (1954).
The production of the thiol group also provides a convenient route for the production of compounds wherein R1 is hydrogen. The thiol may be desulfurized, for example, by refluxing with Raney nickel in absolute alcohol or dioxane, for example, as described by R. L. Augustine xe2x80x9cCatalytic Hydrogenationxe2x80x9d Marcel Dekker Inc., New York 1965 pp 131-133.
Production of a galanthamine analogue where R2 is an alkanoyloxy or benzoyl group can be obtained by a simple esterification reaction. Compounds wherein R2 is alkyloxy, aryloxy, aralkyloxy or alkaryloxy may be formed by forming a salt of the alcohol by reaction with sodium and thereafter reacting the salt with alkyl or other halide as described above for alkylating a phenol salt to produce R1 as other than methyl.
Similarly, reaction of the hydroxy group with an aryl or alkyl isocyanate will produce compounds wherein R2 is a monoaryl or monoalkyl carbamate.
In other transformations of the R2 group, the first step in modification will normally be conversion of the allylic alcohol into an allylic bromide by reaction with bromine or an alkyl bromide. This may be effected by reaction with a slight excess of carbon tetrachloride and triphenylphosphine in a solvent such as methylene chloride at reduced temperature, for example, around 0xc2x0 C. The bromide may then be reacted with magnesium in a Grignard reaction and the Grignard reagent obtained reacted with water to produce a compound wherein R2 is hydrogen. Alternatively, reaction of the allylic bromide with lithium aluminum hydride may achieve the same product.
The allyl bromide may also be used as an intermediate for the introduction of other groups into the C ring. For example, the bromide will react with nucleophiles such as sodium or potassium hydrosulfide to replace the bromo group by a hydrosulfuryl group or with sodium cyanide to introduce a cyano group. The hydrosulfuryl group may be converted into a salt and alkylated in the same ways as can a hydrosulfuryl group in the A ring.
The allylic hydroxyl group may also be converted into a keto group. This can be accomplished, for example, by reaction with Jones reagent (H2CrO4, H2SO4 water and acetone). Proceeding via the keto group may also be an alternative route to production of compounds wherein R2 is hydrogen. For example, the keto compound may be reacted with ethane dithiol and boron trifluoride etherate and the 1,3-dithiolane produced then desulfurized by reaction with Raney nickel.
The ketone intermediate may also be used as a source for compounds wherein R2 is amino, such compounds being obtained by reductive amination of the keto group with ammonia and hydrogen in the presence of a nickel catalyst.
Further analogues that can be obtained by use of the ketone as an intermediate are those wherein R4 is other than hydrogen. These can be obtained by reaction of the ketone with a Grignard reagent.
The ketone may also be used as an intermediate for the production of compounds wherein R7 is hydroxy methyl by first effecting an xcex1-bromination of the ketone and then converting this to hydroxy methyl.
When R2 and R4 jointly form a semicarbazone this can be formed from the ketone by reaction with semicarbazide.
The corresponding oxime and phenylcarbazones may also be obtained from the keto compound by reaction with hydroxylamine and phenylhydrazine respectively.
In order to produce compounds wherein R3 is other than methyl, galanthamine is first demethylated to produce a compound wherein R3 is hydrogen. Demethylation may be effected by reaction with a chloroformate such as methyl chloroformate or phenyl chloroformate to produce a carbamate which may then be cleaved with hydrazine, or by reaction with xcex2,xcex2,xcex2-trichloromethyl chloroformate followed by reaction with zinc and acetic acid. In an alternative N-demethylation route, the hydroxy group is first protected by acetylation and the acetyl ester then reacted with 1-chloroethyl chloroformate in a halogenated solvent to replace the N-methyl group by a xe2x80x94COOCHClCH3 group which may itself be removed by heating in methanol. The resulting amine may then be alkylated with other alkyl groups, branched or unbranched, alkylphenyl group or alkylheterocyclic groups. This reaction may be carried out by converting xe2x80x94NH to the corresponding sodium or potassium salt (NaH, KH) and treating the salt with the corresponding halide, preferably iodides, but bromides and chlorides might be used. All the halides used are commercially available. The reaction conditions may be modified for less reactive halides such as chlorides or aryl or heterocyclic halides which may also be less reactive. For instance, a special method is needed for N-phenylation as described by D. H. R. Barton, J. P. Finet and J. Khamsi, Tetrahedron Lett., 28:887 (1987).
A chlorine atom may be introduced to the cyclohexenol ring of galanthamine by reaction with an acid chloride of a strong organic sulfonic acid such as p-toluene sulfonyl chloride. This reaction proceeding with simultaneous elimination of the hydroxyl group to produce: 
which may itself be used as an intermediate to react with nucleophiles such as alkoxides, azides and cyanides to introduce such groups into the ring at the 2 or 4 positions.
It is also possible to change the degree of saturation of the xe2x80x9ccorexe2x80x9d structure of galanthamine. For example, if one forms an allylic bromide in the C-ring as described above, this bromide may be subject to catalytic hydrogenation in the presence of palladium, for example, palladium on carbon in ethanol at room temperature and atmospheric pressure to remove not only the bromine atom, but also to saturate the unsaturated bond in the C ring.
The C-ring may be oxidized to produce a further unsaturated bond by oxidation, for example, by heating with nickel, platinum or palladium at 300-350xc2x0 C. or possibly under milder conditions if acceptors such as maleic acid, cyclohexene or benzene are present.
The oxygen of the B ring of galanthamine may be replaced by Nxe2x80x94Rxe2x80x2 by reaction with ammonia or an amine in the gas phase at high temperatures in the presence of activated aluminum oxide or aluminum silicate as described, for example, in Yu. K. Yur""ev and E. G. Vendel""shtein, Zh. Obshch. Khim., 21: 259 (1951); Chem. Abstr., 45:7564 (1951); Ibid. 23, 2053 (1953); Chem. Abstr., 49: 3120 (1955); H. Sugisawa and K. Aso, Tohoku J. Agr. Res., 10: 137 (1959); Chem. Abstr., 54: 11015 (1960).
R6 substituents may be introduced into the D-ring for example by Procedure No. 4 hereinafter.
Conversion of R6 to hydroxy methyl may be effected by photolysis in the presence of cyanogen chloride to introduce a cyano group. This may be reduced using a Raney nickel catalyst to produce an aldehyde group that can itself be reduced to hydroxy methyl.
Similar conversions can be effected using lycoramine as starting material to produce compounds wherein the C ring is saturated.
In addition to modifying galanthamine, compounds according to the present invention may also be produced by cyclizing an amide of the formula: 
R1, R3 and R4 groups may be selected as desired in the starting material employed. Cyclization is effected by electrochemical oxidation of the type described in U.S. Pat. No. 4,290,862 for preparing narwedine-type enones. The linear precursor in an appropriate solvent with a conductive salt and 2% HBF4 or KC104 or K2CO3 is added to the anode compartment of an electrolytic cell. The cathode compartment and the electrolytic bridge of the reference electrode contains the same anodic solvent and the same percentage of conductive salt. The working electrode is platinum. Oxidation is carried out at 1.3 volts at low temperatures (below 0xc2x0 C.). This procedures after workup of the product affords cyclization products.
Choice of a suitably substituted starting material permits the production of final products where the R4 groups are other than hydrogen.
Procedures
1. Conversion of Oxygen to Nitrogen in Furanoid Ring
This transformation has been accomplished by several authors. Passage of furan and its homologs, or reduced furans with ammonia over alumina, at 400-450xc2x0 C., affords the corresponding pyrroles. With primary, amines the N-substituted pyrrole is obtained. A typical procedure is as follows. The furan derivative is dissolved in liquid ammonia and passed over an alumina catalyst (200 c.c. 4-6 mesh) which has been preheated to 400xc2x0 C.1 Alternatively, a mixture of a furan derivative and ammonia in aqueous-alcoholic medium may be heated at temperature around 110-150xc2x0 C. The reaction proceeds more readily under pressure and therefore can be carried out in an autoclave.2 
1. C. L. Wilson, J. Chem. Soc., 63, (1945). 
2. R. C. Fuson, C. L. Fleming, R. Johnson, J. Am. Chem. Soc. 60: 1994 (1938). 
2. Introduction of xe2x80x94CH2OH at Position 16.
Position 16 is next to the furan ring. This position is equivalent to the xcex1-position of an ether and therefore prone to radical attack by reagents such as oxygen, peroxides, and photochemical reactions.
Irradiation of cyclic ethers in the presence of cyanogen 3.chloride is known to produce xcex1-cyano ethers in good yields.1 Therefore, a similar reaction on galanthamine should introduce a cyano group in this position. The cyano group is known to be converted to an aldehyde with Raney Nickel and formic acid.2 The aldehyde may in turn be reduced with any reducing agents to the hydroxymethyl group.3 
1. E. Muller, H. Huber, Chem. Ber. 96, 2319 (1963). 
2. T. van Es, B. Stakun, J. Chem. Soc. 5775 (1965). 
3. S. R. Sandler, W. Karo, xe2x80x9cOrganic Functional Group Preparationsxe2x80x9d, Vol. 12, 1968. Academic Press, pp. 89-90. 
A typical procedure is as follows. The photolysis is carried out using a mercury lamp S-81 in a water cooled, unfiltered quartz immersion well. A solution of equimolar amounts of galanthamine and cyanogen chloride, in a spectral grade solvent, is irradiated with stirring, in a nitrogen atmosphere, and in a quartz cell. The reaction is irradiated for 2 h in the presence of sodium bicarbonate. The sodium bicarbonate is essential to absorb the hydrogen chloride. Lower yields are obtained in the absence of the reagent.
The final mixture is filtered, concentrated, washed with appropriate reagents and dried. Removal of solvent affords the product.
The cyano derivative obtained is dissolved in 75% (v/v) of aqueous formic acid and treated with a 50:50 Nixe2x80x94Al alloy (Raney type). The mixture is heated for 3 h at 95xc2x0 C., diluted with absolute ethanol-ethyl acetate and filtered through Celite. The filtrate is concentrated, washed with appropriated reagents and dried. Removal of solvent affords the product.
The aldehyde derivative is dissolved in isopropanol and added to a solution of sodium hydroxide and sodium borohydride, dropwise, at such rate that the reaction refluxes gently. After standing overnight, the reaction is worked up as usual.
3. Conversion of xe2x80x94OMe at Position 13 to Other Substituents
The reaction will require demethylation of the methoxy group. Although demethylation of aromatic alkoxy group is considered a standard reaction, this operation may be tricky in polysubstituted systems. A successful approach is the reaction of boron tribromide at 0xc2x0 C.1 The phenol obtained may be converted to a bromide by standard procedure.2 Generation of a lithium anion at this position3 allows a variety of reactions such as treatment with alkyl halides to give alkyl groups, carbon dioxide to afford acids or aldehydes and ketones to give alcohols.
1. S-Y Han, J. T. Gordon, K. Bhat, M. B. Dratman, M. M. Joullie"", Int. J. Peptide Protein Res., 30:652 (1987). 
2. C. E. Kaslow and M. M. Marsh, J. Org. Chem., 12: 456 (1947). 
3. J. Chiarello and M. M. Joullie"", Tetrahedron, 44:41 (1988). 
A typical procedure follows. A 1M solution of boron tribromide is added dropwise to a solution of galanthamine in dry methylene chloride at 0xc2x0 C., under nitrogen. After stirring at 0xc2x0 C. for 3 h, the excess reagent and boron complexes are hydrolyzed by water. The product is obtained by extraction of the aqueous layer with ether. Removal of the solvent affords the compound.
The phenol derivative is mixed thoroughly with phosphorous pentabromide and heated at 70-80xc2x0 C., then at 120xc2x0 C. Hydrolysis with ice and water affords the crude bromo compound which may be recrystallized from an appropriate solvent.
A solution of n-butyl lithium was added dropwise, at xe2x88x9278xc2x0 C., under argon, to the bromo derivative dissolved in tetrahydrofuran and hexamethylphosphoramide to generate the intermediate anion.
To this anion, one may add any alkyl halide to form the corresponding derivative. Alternatively, the solution could be poured over dry ice to afford the corresponding carboxylic acid, or to an aldehyde or ketone to form the corresponding alcohol derivative.
Treatment of this anion with ethyl chloracetate would give the corresponding ethyl carboxymethyl derivative. The above methodology is general to introduce various groups in place of the methoxy group in the aromatic ring (position 13).
4. Conversions in the D Ring
Removal of the methyl group in the D ring of galanthamine can be accomplished by the classical von Braun reaction.1 The reaction may be manipulated to give either demethylation to a secondary amine or to open the ring. Either of these procedures will give rise to new analogs. Ring opening would afford two chains, one at position 10, possibly a bromoethyl groups and one at position 5, a N-methylpropylamine. These could be used to study the effect of disrupting ring D.
1. H. A. Hagerman, Org. Reactions, VII, Chap 4 (1953). 
However, demethylation would serve to introduce functionality in ring D via the formation of an imine. A typical procedure for introduction of substituents in ring D follows. Treatment of N-demethylated galanthamine with tert-butyl hypochlorite at 0xc2x0 C. will afford the N-chloro derivative. This sensitive compound is not isolated but immediately dehalogenated with either sodium methoxide or diazabicycloundecene to afford the highly unstable pyrroline. This intermediate can be treated with nucleophiles3 or with benzoic and, tert-butylisonitrile as described in reference 2.
2. R. F. Nutt, M. M. Joullie"", J. Am. Chem., Soc., 104, 5852(1982). 
3. J. Hausler, U. Schmidt, Liebigs Ann. Chem. 1881 (1979). 
The compounds of the present invention may be used for the treatment of Alzheimer""s disease either in free base form or as the acid addition salts.
The compounds can be administered in any convenient chemical or physical form. For example, they may be administered as pharmaceutically acceptable salts, as long as these do not quaternize the D-ring nitrogen atom. Useful salts include the hydrobromide and hydrochloride.
The compounds or the pharmaceutically-acceptable acid addition salts may be administered to a patient suffering from Alzheimer""s disease orally or by subcutaneous or intravenous or injection. Sustained release delivery mechanisms are particularly useful for administration of the compounds of the present invention, for example, intracerebroventricularly by means of an implanted reservoir by use of sustained release capsules or by means of a trans dermal patch. It may be necessary to begin at lower doses than are ultimately effective.
Certain of the compounds may be only sparingly soluble in water at room temperature and so injectable compositions are normally in the form of an aqueous suspension. If necessary, pharmaceutically-acceptable suspension aids may be employed. Typically, such a suspension will be employed at a concentration of 1-50 mg/ml more commonly 5-40 mg/ml, for example, 5-30 mg/ml or 10-40 mg/ml, typically 20-30 mg/ml of the compound of the present invention. Typical dosage rates when administering compounds of the invention will depend upon the exact nature and condition of the patient. For example, typical dosage rates for administration by injection are in the range 5-1,000 mg per day depending upon the patient. In some cases, even lower dosages such as 0.5 or 1 mg per day may be helpful. For example, divided doses in the range 0.5-5 mg/kg body weight per day may prove useful. Typically, one might administer a dosage of 50-300 mg per day to a patient of a body weight of 40-100 kg, although in appropriate cases such dosages may prove useful for patients having a body weight outside this range. In other cases, dosages as low as 0.1 mg and as high as 500 mg may be appropriate for persons in this body weight range.
The compounds of the invention may also be administered orally, for example, as an aqueous suspension or a solution in aqueous ethanol or as a solid such as a tablet or capsule. Suspensions or solutions for oral administration are typically of about the same concentration as those used for injections. However, it may be desirable when administering the drug orally to use a higher dosage rate than when administering it by injection. For example, dosages up to 200 mg per day may be used, such as dosages in the range 10-60 mg per day. In preparing such tablets or capsules, standard tablet or capsule-making techniques may be employed. The dosage rate of the compound of the invention or its pharmaceutically-acceptable salt will normally be in the same range as for oral administration of a liquid. If desired, a pharmaceutically-acceptable carrier such as starch or lactose may be used in preparing tablets. Capsules may be prepared using soft gelatine as the encapsulating agent. If desired, such capsules may be in the form of sustained release capsules wherein the main capsule contains microcapsules of active compound which release the contents over a period of several hours thereby maintaining a constant level of active compound in the patient""s blood stream.
The following test provides a good animal model for Alzheimer""s disease in humans: A selective lesion is placed in a subcortical nucleus (nucleus basalis of Meynert) with a resultant cortical cholinergic deficiency, similar in magnitude to that seen in early to moderate stage Alzheimer""s disease. Numerous behavioral deficits, including the inability to learn and retain new information, characterizes this lesion. Drugs that can normalize these abnormalities would have a reasonable expectation of efficacy in Alzheimer""s disease. Haroutunian, V, Kanof P, Davis, K L: Pharmacological alleviations of cholinergic-lesion-induced memory defects in rats. Life Sciences, 37:945-952 (1985).
The following specific formulations may find use in treatment of Alzheimer""s disease:
Tablets or capsules containing 0.1, 0.5, 1.0, 5, 10 and 25 mg hydrobromide of a compound according to the invention to be taken four times a day, or a sustained-release-preparation delivering an equivalent daily dose.
Parenteral solution containing 5 mg/ml.
Liquid formulation for oral administration available in 5 mg/5 ml and 25 mg/5 ml concentration.
There have been reports that galanthamine can cause cardiac arrythmias. If such problems occur with the compounds of the present invention, it may be desirable to administer compounds of the invention in conjunction with another drug such as propantheline bromide to control such arrythmias. As with other drugs that act on the central nervous system, minor side effects, such as nausea, may be noted. In this case, the compounds of the present invention will be administered in conjunction with an agent for control of such side effects.
A substantial proportion of patients suffering from Alzheimer""s disease exhibit not only reduced levels of acetyl choline but also of norepinephrine in the brain. In such cases, the compounds of the present invention may advantageously be employed in conjunction with compounds such as clonidine desipramine, monoamine oxidase inhibitors, methamphetamine and methyl phenidate that stimulate the noradrenergic receptors in the brain.
The production of compounds of the present invention is illustrated by the following Examples: